This application represents the Phase II version of SBIR grant R43 AR049621 entitled "Non-Irritating Retinoids for the Treatment of Aging Skin". Studies carried out prior to Phase I and during the Phase I portion of this project have demonstrated that a synthetic retinoid (identified as MDI-301) is as effective as all-trans retinoic acid (RA) in stimulating collagen repair in the dermis of mice (topically treated) and human skin (in organ culture) but, unlike RA, is non-irritating. We expect, therefore, that MDI-301 will ultimately provide a non-irritating alternative to RA for topical use in the prevention and treatment of aged/photoaged skin. In this Phase II application, we have identified a number of critical issues that need to be addressed as part of the development process of MDI-301. The three specific aims of this Phase II application identify the issues and our approach for addressing each of them. In Specific Aim I we will compare MDI-301 and RA for ability to stimulate extracellular matrix production and inhibit extracellular matrix degradation in human skin transplanted to severe-combined immunodeficient (scid) mice. As part of these studies, we will determine if treatment results in a histologically-evident improvement in the structure of the transplanted skin and determine if function (i.e., wound-healing capacity) is concomitantly improved in the treated skin. In Specific Aim II, MDI-301 and RA will be compared for their ability to modulate events in human skin that contribute to irritation. The information from theses studies will be used to help understand, at the cellular and molecular levels, why MDI-301 is non-irritating under conditions in which RA is irritating. Finally, in Specific Aim III, we will begin the safety evaluation of MDI-301 necessary to file an Investigational New Drug (IND) application with the FDA. The major goal of the Phase II effort is to develop MDI-301 to the point where we can attract a drug-development partner having the resources to obtain regulatory approvals (IND, clinical trials, NDA) and to market the drug effectively.